The goal of this research project is to learn more about the regulation of cardiac muscle cell proliferation, differentiation and hypertrophy using both neonatal and adult rat primary culture systems and transgenic transplant tumor atrial myocytes. We are especially interested in the mechanisms involved with the reinitiation of DNA synthesis in the terminally differentiated adult cell when placed in culture and as stimulated by TPA and the reinitiation of DNA synthesis in transgenic mice myocytes. Another major objective is to learn more about how the structure of these heart muscle cells relates to their function using our preliminary results with TPA and cyclic AMP as models. The rationale being to alter structure and look for changes in function. The specific aims are: 1) To establish the temporal order of expression of protooncogenes, muscle-specific, cell cycle-specific, and cytoskeleton genes when neonatal cardiac muscle cells are placed in culture and as influenced by cyclic AMP. 2) To establish the temporal order of expression of the genes in 1) when adult cardiac muscle cells are placed in culture during the period of dedifferentiation and redifferentiation and as influenced by TPA. 3) To determine the expression of these genes in transgenic myocytes at various phases during the cell cycle. 4) To characterize temporally the ultrastructural changes which are occurring in these cell culture systems and how these changes in ultrastructure correlate with the temporal pattern of expression of the genes specified in 1). 4) To compare the expression of these genes in these different culture systems to each other and to the differentiating in vivo cell to determine if we can establish a pattern of expression of these genes which will indicate how they may function in the control of the proliferation and differentiation of the cardiac myocyte. What we would like to do is establish a cause and effect relationship between structure and function. If we can understand the mechanisms which control the differentiation and proliferation of the heart muscle cell, then it may be possible to design procedures which can be used to initiate or expedite repair or regeneration of the adult myocardium following injury such as that caused by a myocardial infraction.